Key Clinical Summary: The Role of Endocrine Therapy ± CDK4/6 Inhibitors in HER2+/HR+ MBC 1L Setting

This is a micro-learning module summary of the session by Rupert Bartsch, MD, which you can find here. Before participating, please read our CME and disclosure information which can be found here.

Acknowledgment: This program is supported by an independent education grant from Pfizer Global Medical Grants. This online education program has been designed for healthcare professionals globally.

Introduction

This summary explores evolving strategies in human epidermal growth factor receptor 2 (HER2)‑positive metastatic breast cancer (MBC), focusing on the interplay between hormone receptor (HR) signaling and HER2 blockade. It reviews mechanistic data on bidirectional cross‑talk between HER2 and estrogen receptor pathways, clinical trial evidence for endocrine therapy and CDK4/6 inhibitors in combination with HER2‑directed agents, and emerging antibody–drug conjugate (ADC) approaches. The report highlights biomarker‑driven patient selection, outcomes from pivotal studies, and ongoing questions regarding sequencing, maintenance, and central nervous system (CNS) disease management.

Hormone Receptor (HR) Biology and Cross‑Talk with HER2

• For many years, HR status was underappreciated in HER2‑positive disease. Preclinical data demonstrate that growth factor signaling, particularly via mTOR, can phosphorylate and activate estrogen receptor (ER) pathways even in the absence of estrogen, driving resistance to endocrine therapy.
• Conversely, HER2 inhibition can upregulate ER signaling, underscoring the rationale for dual blockade. Optimal outcomes are achieved when both HER2 and ER pathways are simultaneously suppressed, forming the basis for combined endocrine and HER2‑targeted strategies.

Clinical Evidence for Endocrine Therapy with HER2 Blockade

• PERTAIN trial: This trial compared an aromatase inhibitor plus trastuzumab versus an aromatase inhibitor plus trastuzumab and pertuzumab, with or without induction docetaxel or paclitaxel. The dual antibody regimen improved progression‑free survival (PFS) across subgroups. Notably, in patients who did not receive induction chemotherapy, median PFS reached 22 months, highlighting the feasibility of chemotherapy‑free regimens in selected populations.
• DETECT V trial: This trial evaluated endocrine therapy plus trastuzumab/pertuzumab, with or without ribociclib. Sequential cohorts suggested that adding CDK4/6 inhibition improved PFS and OS, though not in a randomized comparison. These findings support the biological rationale for CDK4/6 inhibitors in HER2‑positive/HR‑positive disease.

Case Illustration and CNS Disease

• A representative patient with HR‑positive, HER2‑positive MBC achieved a durable response with induction docetaxel plus trastuzumab/pertuzumab, followed by letrozole maintenance. Addition of ribociclib further extended disease control until CNS progression.
• Smaller phase 2 studies (e.g., DEBORAH, TUXEDO‑1, DESTINY‑Breast12) demonstrate that large molecules such as trastuzumab deruxtecan (T‑DXd) are active in overt brain metastases, where the blood–brain barrier is disrupted. This supports ADCs as effective options for CNS disease, though prevention remains elusive.

CDK4/6 Inhibitors in HER2‑Positive Disease

• Preclinical data show activity of CDK4/6 inhibitors in HER2‑positive cell lines. Clinical trials include:
• MonarchHER: In heavily pretreated patients, abemaciclib plus fulvestrant and trastuzumab achieved the longest PFS and highest response rates compared with endocrine therapy plus trastuzumab or chemotherapy plus trastuzumab.
• PATRICIA (cohort C): Palbociclib plus endocrine therapy and trastuzumab improved PFS compared with physician’s choice in luminal breast cancer.
• AFT-38 PATINA: After induction chemotherapy plus trastuzumab ± pertuzumab, patients randomized to endocrine therapy with or without palbociclib showed a median PFS of 44 months with the quadruplet regimen, establishing CDK4/6 inhibition as a guideline‑endorsed option, despite lack of formal regulatory approval.

Emerging Antibody–Drug Conjugates and Novel Antibodies

• Biparatopic antibodies: Agents such as zanidatamab, designed to bind multiple HER2 epitopes, enhance receptor internalization and possibly synergize with ADCs.
• DESTINY‑Breast07: Evaluated T‑DXd alone or with pertuzumab in the first‑line setting. While the combination showed higher response rates, toxicity was increased, and prior data with ado-trastuzumab emtansine (T‑DM1) plus pertuzumab did not demonstrate superiority over T‑DM1 alone. The incremental benefit of adding pertuzumab to T‑DXd remains uncertain.
• DESTINY‑Breast09: Demonstrated superiority of T‑DXd plus pertuzumab over taxane plus trastuzumab plus pertuzumab, though results from the single‑agent T‑DXd arm are awaited. Duration of T‑DXd therapy and long‑term toxicity remain open questions.

Maintenance Strategies and Sequencing

• Novel trials such as Demether are investigating induction T‑DXd followed by trastuzumab maintenance, with or without additional agents such as CDK4/6 inhibitors or TKIs.
• These approaches aim to balance efficacy with toxicity and explore whether maintenance strategies can reduce CNS relapse risk.
• Sequencing decisions increasingly depend on prior exposure to trastuzumab, pertuzumab, and T‑DM1, with upfront T‑DXd reserved for patients relapsing after optimal perioperative HER2‑directed therapy.

Conclusions

HER2‑positive MBC has seen dramatic survival improvements with HER2‑targeted therapies. While the CLEOPATRA regimen of docetaxel, trastuzumab, and pertuzumab remains a cornerstone, integration of endocrine therapy and CDK4/6 inhibitors has reshaped standards for HR‑positive disease, as evidenced by PATINA. ADCs such as T‑DXd are redefining sequencing, offering potent systemic and CNS activity, though questions remain regarding optimal duration and combination strategies. Future directions include biomarker‑guided de‑escalation, novel biparatopic antibodies, and maintenance approaches that minimize chemotherapy exposure while sustaining long‑term disease control.

Content is accurate as of the date of release on 6 January 2026.